METABOLIC, IMMUNE-MEDIATED, AND TOXIC NEUROPATHIES

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CHAPTER 83 METABOLIC, IMMUNE-MEDIATED, AND TOXIC NEUROPATHIES

Acquired peripheral neuropathy is a highly prevalent and often overlooked condition. Most patients and many physicians are not sufficiently aware of the range of disorders associated with neuropathy outside of the most common cause—diabetes mellitus. Although many neuropathies, including the roughly 30% that have no discernible cause, have no effective treatment, symptomatic therapy is available and therapeutic options are continually expanding. In contrast, many disorders discussed in this chapter can be potentially reversed or at least slowed by treating the underlying condition, removing offending toxins or medications, or limiting immune-mediated injury. For this to happen, proper diagnosis is essential. Several immune-mediated neuropathies are included here, but other important types of neuropathy are not discussed or are considered in more general sections on specific topics. Noteworthy examples include paraneoplastic neuropathy, hereditary and acquired amyloidosis, axonal paraprotein- and myeloma-associated, and acute immune-mediated neuropathies. Topics discussed in other sections include sarcoidosis, environmental toxins, nerve injury, and collagen vascular diseases.

NEUROPATHIES ASSOCIATED WITH DIABETES MELLITUS

Diabetes mellitus is the most common cause of neuropathy in the Western world, as noted since the early 1800s. The most common presentation is distal, predominantly sensory neuropathy; however, diabetes is associated with numerous other forms of neuropathy, ranging from asymptomatic to disabling motor, autonomic, or pain syndromes (Table 83-1). This syndromic list is both clinically and experimentally useful because the differing underlying mechanisms that are likely to occur directly influence treatment choices and efficacy, clinical trial selection, and mechanistic bench research. Most published lists differ slightly in syndrome numbers and entity names, and a separate list could be based on probable pathophysiological mechanisms.¹ Important clinical features include nerve modalities, symmetry, speed of onset, distribution, and related diabetic complications, especially renal failure. A consensus statement in 2005 reviewed clinical syndromes, pathogenic mechanisms, and recommended treatment.² There is growing evidence that symptomatic peripheral neuropathy can occur in the presence of mild diabetes or glucose intolerance even in the absence of notable damage to other end organs. However, in most large series, neuropathy is associated with both retinopathy and nephropathy.³ Less common forms of diabetic neuropathy are not associated with diabetic complications, suggesting a different pathophysiology, such as inflammatory or immune-mediated injury. Conversely, the coexistence of diabetes and neuropathy in a particular patient is not in itself proof of diabetic neuropathy, as unrelated processes may be present that warrant appropriate diagnostic investigation. In general, any of the entities listed can occur with either type 1 or type 2 diabetes (Table 83-1).

TABLE 83-1 Clinical Neuropathy Patterns Associated With Diabetes Mellitus

Distal Diabetic Polyneuropathy

Foot numbness and paresthesia have gradual onset and ascend slowly. The process can spread to the hands, arms, trunk, and scalp in advanced cases, but more commonly hand and arm involvement is caused by superimposed processes, such as compressive mononeuropathy.³ Loss of light touch, pain, and temperature precede loss of proprioception; distal weakness and atrophy are late findings. Patients generally notice “positive” or unpleasant symptoms, especially burning pain, electrical or stabbing sensations, paresthesia, and deep pain; loss of sensation and anesthesia are less common. Symptoms are frequently worse at night when there are less sensory distractions. Approximately 20% to 50% of diabetic patients have at least one symptom of diabetic neuropathy but even more have asymptomatic disease. Lack of sensation can lead to unperceived injury, ulcers, and Charçot joints—a significant form of morbidity. Not surprisingly, objective evidence of functional loss on clinical examination and laboratory testing often exceeds symptoms. Onset may occur after several years of diabetes or with subclinical diabetes, and the neuropathy may lead to the discovery of underlying diabetes. Sensory fibers in the foot and distal leg are predominantly affected, especially small diameter sensory and autonomic fibers. Examination of the lower leg usually reveals loss of vibration, pressure, pain, and temperature perception (both small and large fiber-mediated) and absent ankle deep tendon reflexes. Signs of peripheral autonomic (sympathetic) dysfunction are frequent, including altered skin temperature (cold or warm), dry, often scaly, skin, and calluses in pressure-bearing areas. Loss of sensation for 128-Hz vibration, monofilament touch, and loss of ankle jerks are considered 87% sensitive for detecting neuropathy and predicting foot ulcer.² The diagnosis is ultimately clinical and requires exclusion of other reasonable causes of neuropathy. Even if symptoms remain confined to the legs and feet, objective testing such as nerve or skin biopsy and clinical electrophysiological studies often show evidence of more widespread involvement. Electrodiagnostic studies are an important adjunct to assess severity and to parse out superimposed mononeuropathy, regional syndromes, superimposed radiculopathy, and demyelinating neuropathy. Nerve biopsy is not routinely necessary but in some cases it demonstrates signs of microvascular changes in addition to axonal loss (Fig. 83-1). Skin punch biopsy to assess epidermal nerve fiber density is increasingly available and minimally invasive, as discussed later.

Figure 83-1 Diabetic neuropathy, sural nerve. The tissue section of the nerve shows a mild loss of myelinated fibers. Endoneurial microvessels show a collar of hyaline pink material, a characteristic feature of diabetic microangiopathy (semithin plastic sections, toluidine blue-basic fuchsin).

(Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

Diabetic autonomic neuropathy affects up to one half of diabetics.³ Genitourinary and sexual dysfunction, such as impotence, are most common, but orthostatic intolerance and hypotension, gastrointestinal dysmotility (diarrhea or constipation), gastroparesis, fatigue and exercise intolerance, vasomotor disturbance, and pupil dysfunction are also common. Patients with diabetic autonomic neuropathy have shorter survival than do unaffected diabetic patients, but the relative risk is less than early reports suggested. Patients may become intolerant of autonomically active medications, such as antihypertensive or anticholinergic agents, as the neuropathy slowly worsens, producing symptoms such as orthostatic complaints, syncope, urinary retention, excessively dry eyes, and focusing difficulties. Formal autonomic testing is widely available and is especially helpful when the clinical picture is equivocal or the cause of orthostatic symptoms is unclear. Treatment and assessment are discussed in Chapters 29 through 32 Chapter 30 Chapter 31 Chapter 32. The pathophysiology is presumed to be the same as in distal diabetic polyneuropathy and is discussed later.

Ischemic mononeuropathies are presumably due to occlusion of arterioles supplying individual nerves and produce acute ischemia and aching pain, followed by loss of nerve function. The process can affect either cranial or peripheral nerves or nerve roots. Pupil-sparing oculomotor palsy is the most common cranial neuropathy, followed by sixth and seventh neuropathies, but all are relatively uncommon. Diabetics are more susceptible to compression or entrapment neuropathy, and at least 30% of diabetics have carpal tunnel syndrome, which can range from asymptomatic to very distressing.¹ Ulnar neuropathy at the elbow, peroneal neuropathy at the fibular head, and lateral femoral cutaneous neuropathy (meralgia paresthetica) are also common.

Diabetic amyotrophy (diabetic radiculoplexus neuropathy) is a monophasic illness seen primarily in type 2 diabetic patients and characterized by subacute proximal leg weakness progressing stepwise over weeks to months, weight loss, atrophy, and aching proximal leg pain. The weakness affects mostly but not exclusively the femoral and obturator nerve distributions, plateaus over weeks, and slowly improves over 12 to 36 months.⁴ Sensory involvement is less marked and often overshadowed by the underlying distal polyneuropathy. Anatomic boundaries are not respected, and there is often evidence of both nerve root and plexus involvement, hence the descriptive label. Findings may be unilateral or bilateral but asymmetric. If involvement is extensive, a diagnosis of chronic inflammatory demyelinating polyneuropathy, which is more common in diabetic patients, should be considered. Thoracic and cervical forms also occur but are less common and must be distinguished from ischemic injury and unrelated compressive spine disease. Although various neuropathological findings have been reported, an immune-mediated process is suspected and a long-awaited treatment trial is ongoing.

Etiology

There are numerous lines of evidence and hypotheses attempting to explain diabetic polyneuropathy but most start with perturbations initiated by excessive glucose levels. Duration of diabetes, hemoglobin A1c levels, and other signs of poor glucose control correlate with neuropathy development and severity. Microvascular injury appears to be a crucial process in the development of neuropathy as well as in damage of other end organs, and interruption of this process has long been a target of therapeutic intervention. Four major pathways of glucose metabolism are implicated. Excess intracellular glucose is processed, in part, through the polyol pathway in a series of reactions catalyzed by aldose reductase. This pathway leads to sorbitol and fructose accumulation, NAD(P)H-redox imbalances, changes in signal transduction, and excessive production of reactive oxygen radicals.⁵ Also, nonenzymatic glycation of proteins produces advanced glycation end products in peripheral nerve, and these impair axonal transport, neurotrophic factor production, and gene expression. In addition, protein kinase C activation starts a cascade of stress responses and increases hexosamine pathway flux; both processes lead to oxygen radical generation.⁵ Specific inhibitors of each pathway, aimed at blocking one or more microvascular complications, have shown considerable promise in rodent models: they include nine different aldose reductase inhibitors, various neurotrophins, blood flow and angiogenesis enhancers, free radical scavengers, and others. Unfortunately, virtually all have failed or have produced equivocal results, but several trials are presently ongoing, including a gene therapy trial of vascular endothelial growth factor. A broader approach targeting several pathways at once may be needed to affect human disease. Other risk factors have gathered recent attention. A large European consortium has found the following independent risks factors for the cumulative incidence of diabetic neuropathy: low-density lipoprotein cholesterol and triglycerides, high body mass index, high von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking.⁶ Several factors are potentially adjustable and some might explain why neuropathy develops in patients with early disease or with simple glucose intolerance, as we discuss later. More acute or subacute entities suggest an immune-mediated mechanism, and some may respond to immunomodulating therapies.

Treatment

Tight glycemic control is the most important and only intervention proved to prevent or limit diabetic polyneuropathy and autonomic neuropathy, but it does not reverse existing nerve injury.^7,⁸ Treatment of other modifiable potential risk factors (lipids, blood pressure, weight) is an evolving but likely important approach. The efficacy of preventative medications currently in clinical trials is yet to be determined.

Numerous symptomatic treatments are effective in reducing—but usually not eliminating—the discomfort of diabetic and other painful polyneuropathies. Randomized double-blind, controlled trials have demonstrated symptomatic relief, primarily for painful neuropathy, with a number of agents, including several tricyclic antidepressants, gabapentin, pregabalin, tramadol hydrochloride, and the serotonin and norepinephrine reuptake inhibitor duloxetine.^1,⁹^–¹¹ The selective serotonin reuptake inhibitor paroxetine was better than placebo but not better than imipramine, and citalopram was similar to paroxetine; fluoxetine showed no significant benefit. However, only pregabalin and duloxetine have received U.S. Food and Drug Administration indications for treatment of painful neuropathy. Numerous other medications and therapies have undergone small randomized or incompletely controlled trials and are empirically used. Proper foot care and prompt attention to injury are essential.

Glucose Intolerance and Neuropathy

There is increasing recognition of impaired glucose tolerance, sometimes designated as prediabetes, in patients with painful sensory neuropathy, as many as 34% in one study.¹²^–¹⁴ Fasting plasma glucose of 100 to 125 mg/dL or 2-hour glucose of 140 to 199 mg/dL (impaired glucose tolerance) defines prediabetes. The 2-hour oral glucose tolerance test is the usual detection method and is recommended in patients with otherwise unexplained sensory neuropathy. Autonomic dysfunction appears to be common in these patients.¹⁵ The mechanism of nerve damage in hyperglycemia is still unknown, but early indications suggest that aggressive lifestyle modifications affect neuropathy progression and are the target of a multicenter clinical trial. Most patients with neuropathy associated with prediabetes are overweight and show metabolic manifestations of insulin resistance. Treatment of hyperglycemia, insulin resistance, neuropathic pain, and individualized diet and exercise counseling have been more effective than glucose-lowering medications in preventing progression from impaired glucose tolerance to diabetes.¹⁴ Diet and exercise also seem to reduce neuropathic pain in these patients.

Other Endocrine Disorders

Hypothyroidism is uncommonly associated with peripheral neuropathy and frequently with carpal tunnel syndrome. Acromegaly is associated with entrapment neuropathy.

Small Fiber Neuropathy

Small fiber neuropathy is an increasingly diagnosed disorder with pure or predominant involvement of small-diameter myelinated and unmyelinated sensory and autonomic nerve fibers and with minimal or no large fiber sensory or motor impairment. Common manifestations include pain, burning distal paresthesia, impaired temperature perception, trophic signs, distal autonomic dysfunction, especially impaired vasomotor and temperature control, and decreased sweating. Diabetes is the most common cause, and findings are indistinguishable from early distal diabetic polyneuropathy. Other important or common causes include amyloidosis, chronic alcoholism, certain toxins, and rare hereditary entities. However, in a substantial group of patients there is no discernible cause.

Because most conventional tests, such as nerve conduction studies, do not assess small-diameter fibers, other objective means to confirm this syndrome are desirable. Quantitative sensory testing assesses small and large sensory fibers by examining temperature and vibratory thresholds; although useful for sequential measures in clinical trials, it is not recommended for routine clinical diagnostic use.^16,¹⁷ Epidermal nerve fiber density measured from skin punch biopsies is rapidly increasing in popularity and availability as a simple and minimally invasive technique. The small skin sample is stained immunohistochemically with antibodies against nerve-specific protein gene product 9.5 (PGP9.5).¹⁸^–²⁰ Most frequently, there is a reduction in nerve fiber numbers, worse distally, but axonal swellings also correlate with disease²¹ (Fig. 83-2). Sensitivity ranges from 74% to 87%. Distal autonomic function measures correlate better with epidermal nerve fiber density than cold perception thresholds and are significantly better than sural sensory nerve amplitude in documenting the selective loss of small diameter fiber function.^17,¹⁹ Quantitative sudomotor axon reflex testing, which evaluates postganglionic sympathetic sudomotor function by measuring evoked sweat after acetylcholine iontophoresis, is the best validated technique in this condition, but other methods are also employed; current clinical and common research methods are listed in Table 83-2. Treatment is similar to that of diabetic and other painful forms of neuropathy covered previously.^20,²²

Figure 83-2 Epidermal nerve fibers of the calf in a normal individual and a patient with small fiber neuropathy. A, Skin biopsy of a healthy person shows two axons that extend perpendicularly to the skin surface toward the layer of keratin. The epidermal nerve fiber density was 10.5 fibers/mm. B, Skin biopsy from a patient with a small fiber neuropathy demonstrating severe loss of epidermal nerve fibers. Some of the few remaining nerve fibers have focal swelling of the axons as exemplified in this image. The epidermal nerve fiber density was 2.0 fibers/mm. Both skin specimens were fixed by periodic acid-lysine-paraformaldehyde and stained by immunoperoxidase method for the panaxonal marker PGP9.5.

(Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

TABLE 83-2 Clinical and Research Tools for Small Fiber Neuropathy Testing

Epidermal nerve fiber density (skin punch biopsy)

Quantitative sudomotor axon reflex testing

Cardiovascular autonomic reflex testing

Quantitative sensory testing

Laser Doppler reflex testing (limited availability)

Sural nerve biopsy electron microscopy small fiber counts (tedious and rarely performed)

Uremic Neuropathy

Neuropathy is associated with chronic renal failure; some patients also have coincident diabetes. This is a distal symmetrical sensorimotor polyneuropathy possibly caused by uncharacterized uremic toxins. It is present in as many as 60% to 70% of patients with chronic renal failure, but patients are often asymptomatic and the neuropathy is identified only by nerve conduction studies.²³ Symptoms are insidious and include painful dysesthesia, stocking-glove loss of sensation, and mild distal muscle weakness. Autonomic dysfunction is generally not as severe as with diabetes. Neuropathy typically occurs when the glomerular filtration rate falls below 20 mL/min and undialyzable toxins accumulate.²⁴ Sensory and motor conduction velocities are mildly reduced, and evoked motor and sensory nerve response amplitudes are reduced. Pathologically, there is axonal degeneration of the most distal nerve trunks with secondary segmental demyelination.

Without dialysis or renal transplantation, prognosis is poor and the neuropathy progresses. With peritoneal or hemodialysis, the neuropathy stabilizes. Improvement after transplantation, sometimes with complete resolution of symptoms in as few as 1 to 3 months, is reported.^25,²⁶

Neuropathy Associated With Hepatic Disease

Peripheral neuropathy is rarely associated with primary liver diseases. A painful sensory neuropathy is associated with primary biliary cirrhosis and is probably caused by xanthomas forming in and around nerves. Infectious diseases of the liver and hereditary disorders with liver involvement (porphyria) are also associated with peripheral neuropathy but are discussed elsewhere. Immune-mediated diseases, such as polyarteritis nodosa and sarcoidosis, may cause both liver dysfunction and neuropathy, notably mononeuropathy multiplex.

SELECTED CHRONIC IMMUNE-MEDIATED NEUROPATHIES

Acquired Chronic Immune-Mediated Neuropathies

There is some disagreement on which entities in this category should be grouped under the unifying term chronic inflammatory demyelinating neuropathy and which variants should be separated into discrete entities. The definitive diagnosis of the classic form of chronic inflammatory demyelinating neuropathy is also debated and a number of diagnostic criteria have been proposed.²⁷^–³² The cardinal features of classic chronic inflammatory demyelinating neuropathy include progressive symptoms for more than 2 months (to differentiate from Guillain-Barré syndrome), predominant motor findings, symmetrical distal and proximal arm and leg involvement, reduced or absent deep tendon reflexes, increased cerebrospinal fluid protein, primary signs of demyelination on electrodiagnostic studies, and segmental demyelination on nerve biopsy. Not all treatment-responsive patients have all clinical or laboratory characteristics. Elevated cerebrospinal fluid protein and nerve biopsy are not required by all classifications. Magnetic resonance imaging may demonstrate gadolinium enhancement or increased T₂-signal abnormalities in proximal nerves or nerve roots.

The stringent 1991 American Academy of Neurology subcommittee criteria were intended for uniformity in clinical trial enrollment, not for routine clinical application, but were used for lack of widely accepted scales ³¹; more recent criteria deemphasize some features, sacrificing specificity to improve sensitivity.^30,³² The cited prevalence is 0.5 of 100,000 children and 1 to 2 of 100,000 adults.²⁹ The course may be relapsing or progressive but relapsing forms are more common in younger patients.³³ Secondary axonal loss occurs, likely as a concomitant injury, but is critical for treatment response, long-term disability, and prognosis. Early effective treatment is the best means to limit this process.

Pathogenesis

An autoimmune process with activation of autoreactive T and B cells is presumed but specific targets have not been identified. The migration of activated T cells across the blood-nerve barrier is being actively investigated. Autoantibodies are also presumed to exist, and sera from chronic inflammatory demyelinating neuropathy patients do induce conduction block in animals, but specific antibodies have not been identified other than in some well-defined syndromes.

Treatment

Randomized controlled trials have demonstrated the effectiveness of corticosteroids, plasmapheresis, and intravenous immunoglobulin and found no significant difference between these treatments, but intravenous immunoglobulin and steroids are recommended as first line treatment.³⁴ Most studies, however, have been short in duration. Interferon β-1a was effective in open label but not in controlled trials of treatment-resistant patients. Adhering to published criteria does not seem to predict treatment responsiveness.³⁵ Use of other medications is supported by open trials or empiric use: these include azathioprine, cyclophosphamide, mycophenolate mofetil, etanercept, and cyclosporin A. To further complicate matters, a rare treatment-responsive chronic inflammatory demyelinating neuropathy-like illness appears to be triggered by the immunomodulatory agents interferon-α or -β, tumor necrosis factor α antagonists, tacrolimus, and cyclosporin A.